Lopinavir is chemically known as (αS)-N-[(1S,3S,4S)-4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide and structurally represented by Formula (I).

Ritonavir is chemically known as [5S-(5R*,8R*,10R*,11R*)]-10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester and structurally represented by Formula II.

Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants. Some of the more important retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, human T-cell lymphotrophic viruses, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
Lopinavir is known to have utility for the inhibition of HIV protease and the inhibition of HIV infection. However, Lopinavir is not effective for the treatment of HIV infection when administrated alone. Lopinavir is particularly effective for the inhibition of HIV protease and for the inhibition of HIV infection when co-administered with Ritonavir. Lopinavir, when combined with Ritonavir, is also particularly effective for the inhibition of HIV infection when used in combination with one or more reverse transcriptase inhibitors and/or one or more other HIV protease inhibitors. Lopinavir is indicated in combination with Ritonavir for the treatment of HIV-infection and is manufactured under the trade name of Kaletra®.
Ritonavir is an inhibitor of the HIV-1 and HIV-2 proteases with in vitro and in vivo activity against the Human Immunodeficiency Virus (“HIV”), and is presently sold in a soft gelatin capsule dosage form for oral administration under the trade name Norvir® and is indicated for use in combination with other antiretroviral agents for the treatment of HIV-infection.
(2S,3S,5S)-5-Amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) or an acid addition salt thereof is an useful intermediate for preparing compounds with antiviral activity such as Lopinavir and Ritonavir.

Abbott Laboratories has disclosed compound of Formula (III) in U.S. Pat. No. 5,491,253. U.S. Pat. No. 5,491,253 discloses a process for the preparation of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III), which comprises, reducing (5S)-2-amino-5-N,N-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene (IV) with sodium borohydride in presence of methane sulfonic acid to produce (2S,5S)-2-amino-N,N-dibenzylamino-4-oxo-1,6-diphenylhexane (V), which is further reduced using sodium borohydride in trifluoroacetic acid to produce (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III). The process is shown in the scheme-1.

Journal of Organic Chemistry 1995, 59, 4040-4041 discloses a similar process for the preparation of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) with optimized mole ratio of sodium borohydride and methane sulfonic acid to produce (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) with diastereomeric mixture of 93:7.
Organic Process Research and Development 1999, 3, 94-100 also discloses a process for the preparation of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) using sodium tris(trifluoroacetoxy)borohydride and trifluoroacetic acid to produce (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) diastereoselectively (84%) with 83% yield.
(2S,3S,5S)-5-Amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) prepared by the above prior-art processes is typically an oily mass and it is contaminated with undesired impurities, which are carried forward, as impurities, to the finished product Lopinavir/Ritonavir. Removal of these impurities in the final stage is often proved to be difficult and requires repeated crystallizations, which finally results in the low yield of Lopinavir and Ritonavir.
Hence, there is a need to develop a process, which provides (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) a key intermediate in the preparation of Lopinavir and Ritonavir with essentially high purity.
The present invention specifically directs to the purification of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) by making its crystalline acid addition salt, which can be used as such to produce Lopinavir/Ritonavir with high purity and yield.